诱发眼震电图动态监测小脑出血的应用基础研究
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摘要
研究背景
在我国的城镇居民中,脑血管疾病已成为患者死亡的首要原因,其中颅内出血(intracerebral homorrhage,ICH)约占脑卒中患者的15%,发病一个月内死亡率约为50%,而且发病年龄越来越年轻化。在ICH患者中,有5-10%的患者出血部位在小脑,最终致死率高达20-30%。通过尸检发现,小脑出血患者的死亡主要是出血和水肿形成脑疝,造成对脑干的压迫和破坏所引起的。所以及早判定患者病情变化和及时采取临床干预措施是治疗疾病、挽救生命的关键。
目前,脑CT是诊断小脑出血最可靠的检查方法,但它较少用于连续动态检查,如果反复检查,费用较高,且需要运送患者,在不方便的同时也可能引起患者病情的恶化。现在,在临床上缺乏对小脑出血患者的病情发展进行床旁动态监测及对病情是否波及脑干进行预判的方法和手段。本实验研究一种临床监测手段,它具有床旁、动态、无创、简单、客观、准确的优点。最重要的是,它既能够在小脑出血和水肿侵犯脑干时进行判断,又能够监测小脑出血和水肿对脑干由刺激到破坏的动态过程,为临床医生及时判断患者病情变化和及早进行临床干预提供了可能。
目的
1建立稳定的小脑半球出血大鼠模型,观察和总结不同程度出血大鼠在术后72h的自发眼震和冰水诱发眼震电图( ENG ,electronystagmogram)的变化特点和规律,观察模型大鼠枕大池压力(pressure of cisterna magna,PCM)和脊髓蛛网膜下腔压力(pressure of spinal subarachnoid space,PSSS)及压力差,探讨利用ENG监测小脑出血病情变化和预先判断小脑脑疝发生的可行性。
2观察小脑半球出血模型大鼠脑干眼动相关神经核团(脑桥旁正中网状结构(paramedian pontine reticular formation,PPRF)、前庭神经核(vestibular nucleus,VN)和动眼神经核(oculor motor nucleus,OMN))的神经递质受体GABA-ARα1和NMDAR1变化及相关神经核团的HE染色变化,探讨小脑半球出血继发脑干病变引起自发眼震和冰水诱发眼震异常的神经化学机制。
3观察电刺激及电凝损毁大鼠小脑绒球小结叶(flocculonodular lobe,FL)和顶核(fastigial nucleus,FN)后自发和冰水诱发ENG变化及VN神经递质受体GABA-ARα1和NMDAR1变化,通过与小脑出血引起眼震异常的比较及对VN神经递质受体变化的分析,探讨小脑半球出血引起自发眼震和冰水诱发眼震异常的病理生理基础。
方法
第一部分:小脑半球出血大鼠模型的建立及对眼球震颤的分析
1根据Rosenberg报道的方法,立体定位小脑齿状核,注射Ⅶ型胶原酶建立小脑半球出血大鼠模型。动物随机分为5组:假手术组、0.2UⅦ型胶原酶组、0.4UⅦ型胶原酶组、0.6UⅦ型胶原酶组、0.8UⅦ型胶原酶组,每组8只。在小脑半球出血大鼠模型建立72h时,采集以下指标
2使用RM6240C多道生理记录仪记录其自发和冰水诱发ENG。
3分别测量其枕大池和脊髓蛛网膜下腔压力,并计算二者间的压力差。
4使用4℃多聚甲醛灌注固定大鼠,取出脑组织,以针道所在中心,穿刺平面前后,切片机作冠状切片,常规HE染色,根据公式计算血肿面积。
5处死大鼠,剥离颅骨取出脑组织,分离脑干和小脑,使用干湿重法测定小脑半球出血后脑组织含水量。
第二部分:小脑半球出血模型大鼠自发和冰水诱发眼震的神经化学机制研究
1通过免疫组化法观察模型大鼠PPRF、VN和OMN抑制性神经递质受体GABA-ARα1和兴奋性神经递质受体NMDAR1变化情况。
2通过HE染色镜下观察模型大鼠小脑及脑干组织病理学改变。第三部分:大鼠一侧小脑绒球小结叶和顶核电刺激及电凝损毁后眼震电图变化
电刺激及电凝损毁大鼠一侧小脑绒球小结叶和顶核,观察其自发眼震和冰水诱发ENG改变及脑干VN神经递质变化。
结果
第一部分:1动物存活率:40只实验大鼠共死亡8只,其中1只因麻醉过量死亡,另外7只死于脑疝,动物存活率为87.5%。
2 PCM、PSSS和两者间的压力差:在术后72h时,0.2U组、0.4U组、0.6U组和0.8U组大鼠PCM、PSSS与假手术组大鼠相比有明显差异(P<0.05),胶原酶注入剂量越大,大鼠PCM、PSSS越高,二者间压力差越大(P<0.05)。
3大鼠模型建立72h自发眼震:在假手术组大鼠未观察到自发震颤,ENG记录可见正弦平滑曲线为扫视眼球运动,未见眼震样锯齿波。所有胶原酶诱导小脑出血模型组大鼠72h均出现自发性眼震。0.2U组大鼠可观察到旋转性眼震,在ENG上为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震;0.4U组大鼠也表现为旋转性眼震,其方向与0.2U组大鼠相反;0.6U组大鼠出现了快相向左,慢相向右的水平性自发性眼震,伴有间断性发作的快相向上、慢相向下或者快相向下、慢相向上的垂直性眼震;0.8U组大鼠死亡前眼球固定,未记录到自发眼震,ENG呈一条直线。
4大鼠模型建立72h冰水诱发眼震:假手术组大鼠一侧冰水诱发后可见快相向冰水对侧,慢相向冰水侧的水平跳动性眼震。0.2U组大鼠右侧冰水诱发为快相向左、慢相向右的水平为主伴有垂直方向的眼震,其潜伏期(Lat,latency)与假手术组比较无差异(P>0.05),频率(F,Frequency)(P<0.05)、波幅(Amp,amplitude)、慢相角速度(SPV,slow-phase velocity)及变异系数(CVI,circadian variation index)均高于假手术组(P<0.01)。左侧冰水诱发眼震在水平方向上与右侧冰水诱发方向相反,Lat较假手术组延长(P<0.01),F、Amp、SPV均低于假手术组(P<0.05),CVI增大(P<0.01)。0.4U组大鼠右侧冰水诱发眼震在水平方向上与0.2U组相同,Lat较假手术组延长(P<0.01),Amp(P<0.05)、F、SPV均低于假手术组(P<0.01),CVI增大(P<0.01);左侧冰水诱发眼震在水平方向上与0.2U组相同,Lat与假手术组比较无差异(P>0.05),F、Amp、SPV及CVI均高于假手术组(P<0.01)。0.6U组大鼠右侧冰水诱发眼震在水平方向上为快相向左,慢相向右的眼震,Lat与假手术组比较无差异(P>0.05),F、Amp(P<0.05)、SPV及CVI均高于假手术组(P<0.01);左侧冰水刺激未诱发出眼震。0.8U组大鼠双侧冰水刺激均未诱发眼震。
5大鼠小脑血肿面积:各造模组大鼠在72h可见注入胶原酶一侧小脑半球肿胀、饱满;部分大鼠脑组织出现移位,中线向对侧偏移,脑干受压扭曲变形。假手术组大鼠注射侧脑组织仅见注射针道,未见血肿及水肿。各造模组可见小脑半球出血,出血中心呈暗红色,出血部位相近,分布均一,周围灰白质分界模糊。不同剂量胶原酶组形成的血肿面积大小不同,其组间对比有统计学差异(P<0.05),注入胶原酶剂量越多,血肿面积越大。
6脑组织含水量:胶原酶注射各组大鼠脑组织含水量测定明显高于假手术组(P<0.05)。胶原酶注射各组大鼠脑组织含水量与胶原酶剂量呈正相关(P<0.05),即胶原酶注入剂量越大,脑组织含水量越多,脑水肿越明显。
第二部分:1脑干眼动相关神经核团递质变化:细胞膜被DAB染成棕黄的阳性细胞在脑干内呈群集样分布,抑制神经递质比( GABA-ARα1/GABA-ARα1+ NMDAR1 )和兴奋神经递质比(NMDAR1/ GABA-ARα1+ NMDAR1)在假手术组脑干两侧PPRF、VN和OMN内无差别(P>0.05);0.2U组大鼠脑干右侧PPRF兴奋神经递质比高于左侧(P<0.05),左侧OMN和VN兴奋神经递质高于右侧(P<0.05);0.4U组大鼠脑干左侧PPRF兴奋神经递质比高于右侧(P<0.05),右侧OMN和VN兴奋神经递质高于左侧(P<0.05);0.6U组大鼠脑干右侧PPRF兴奋神经递质比高于左侧(P<0.05),左侧OMN和VN兴奋神经递质高于右侧(P<0.05);0.8U组大鼠脑干PPRF、VN和OMN神经递质较假手术组及其他造模组表达下降,但右侧PPRF和兴奋神经递质比相对高于左侧(P<0.05),左侧OMN和VN兴奋神经递质相对高于右侧(P<0.05)。
2模型大鼠小脑及脑干组织病理学:光镜下观察HE染色可见造模侧血肿区域内大量红细胞及炎性细胞聚集,血肿中心及周围神经细胞肿胀,体积增大,周围出现空隙;神经纤维排列紊乱、中断、疏松;部分小血管闭塞。胶原酶注入剂量越大,红细胞及炎性细胞聚集越明显,组织疏松水肿范围越大。0.2U及0.4U组大鼠脑干HE染色与假手术组对照无异常,在0.6U组因脑疝死亡的大鼠及0.8U组大鼠的脑干中,可见脑干中纵行和横行的神经纤维组织紊乱、中断及疏松,以脑桥延髓阶段中线结构改变明显;炎性细胞聚集,胞核增大深染,嗜酸性增强,其间散在分布的神经细胞核群内部分细胞出现细胞肿胀,细胞核碎裂或脱失,此改变以脑桥及延髓阶段右侧明显。
第三部分:大鼠右侧绒球小结叶和顶核电刺激及电凝损毁后自发和冰水诱发眼震特点及ENG
1右侧小脑绒球小结叶电刺激后自发和冰水诱发眼震特点及ENG:为旋转性眼震,在ENG上为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震。右侧冰水诱发眼震在形式上表现为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震。ENG表现与正常对照组相比,Lat无差异(P>0.05),F加快、Amp增加,SPV增快和CVI增大(P<0.01);左侧冰水诱发眼震在形式上表现为水平方向上快相向右、慢相向左,垂直方向上为快相向上、慢相向下的眼震,ENG表现与正常对照组相比,Lat延长(P<0.01)、F减慢、Amp和SPV减小(P<0.01),CVI增大(P<0.01)。
2右侧绒球小结叶电凝损毁后自发和冰水诱发眼震特点及ENG:为旋转性眼震,在ENG上为水平方向上快相向右、慢相向左,垂直方向上为快相向上、慢相向下的眼震。右侧冰水诱发眼震在形式上表现为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震,ENG表现与正常对照组相比,Lat延长、F减慢、Amp和SPV减小(P<0.01),CVI增大(P<0.01);左侧冰水诱发眼震在形式上表现为水平方向上快相向右、慢相向左,垂直方向上为快相向上、慢相向下的眼震,ENG表现与正常对照组相比,Lat无差异(P>0.05),F增加、Amp、SPV增大(P<0.01)和CVI增大(P<0.01)。
3右侧顶核电刺激后自发和冰水诱发眼震特点及ENG:大鼠右侧顶核电刺激后出现了快相向右,慢相向左的水平性自发性眼震,伴有间断性发作的快相向上、慢相向下或者快相向下、慢相向上的垂直性眼震。右侧冰水诱发眼震在水平方向上与正常对照组比较无差异,Lat延长,F、Amp、SPV均低于对照组(P<0.01),CVI高于对照组(P<0.01)。左侧冰水诱发表现为快相向右,慢相向左的水平眼震,Lat与正常对照组比较无统计学差异(P>0.05),F、Amp、SPV及CVI均高于正常对照组(P<0.01)。
4右侧顶核电凝损毁后可观察到旋转性眼震,在ENG上为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震。右侧冰水诱发眼震在水平方向上表现为快相向左、慢相向右的眼震,Lat与正常对照组比较无统计学差异(P>0.05),F、Amp、SPV及CVI均高于正常对照组(P<0.01)。左侧冰水刺激诱发眼震在形式上方向与右侧冰水相反,但Lat延长,F、Amp、SPV均低于对照组(P<0.01),CVI增大(P<0.01)。
5右侧绒球小节叶电剌激,脑干右侧VN兴奋神经递质比低于左侧(P<0.05),右侧绒球小节叶电凝损毁后,脑干右侧VN兴奋神经递质比高于左侧(P<0.05)。
6右侧顶核电剌激,脑干右侧VN兴奋神经递质比高于左侧(P<0.05),右侧顶核电凝损毁后,脑干右侧VN兴奋神经递质比低于左侧(P<0.05)。
结论
1应用不同剂量胶原酶立体定向注入大鼠小脑齿状核可以成功构建不同出血量的小脑出血动物模型。
2大鼠小脑的出血量不同,自发眼震和冰水诱发眼震的表现形式也不同。
3大鼠小脑不同的出血量对脑干形成不同的影响,而根据眼震尤其是冰水诱发眼震的不同变化形式可以判定小脑出血后脑干的功能状态。
4 PCM、PSSS升高及两者压力差的存在可能是小脑出血后眼震发生变化的原因。
Background
Cerebrovascular disease is the leading death cause of urban residents in China. Intracranial hemorrhage (intracerebral hemorrhage, ICH) accounts for about 15% of stroke patients, with the mortality about 50% within the first month after attack. The incidence age has become much younger in recent years. The ICH bleeding location of 5-10% of patients is in the cerebellum with the final mortality rate as high as 20-30%. Autopsy studies showed that death of cerebellar hemorrhage was mainly caused by herniation by which the brainstem was oppressed and destructed under the circumstance of the hemorrhage and edema. Therefore, it was critical to monitor the changes of patients’condition and apply early interventional strategy to treated the disease and save lives. At present, CT is the most reliable detecting method for the diagnosis of the cerebellar hemorrhage. However, CT is not a dynamic diagnostic method, whereas the repeated exam to observe the changing condition of the patients increase the the costs. Another disadvantage is the movement of the patients may worse the condition of the patients. A method which can be operated bedside in time is largely needed to monitor the progression of the patients’condition which to discriminate whether the brainstem was intact. The study was to find a clinical useful monitoring method which has the characteristics including bedside, dynamic, non-invasive, simple, objective, accurate. Importantly, it is that it can be applied to anticipate the occurrence of brainstem intact after cerebellar hemorrhage and monitor the dynamic process of the brainstem intact which changed from being stimulated to being damaged.
Purposes
1 The stable cerebellar hemorrhage model in rats was established. The characteristics and changing pattern of electronystagmogram spontaneous nystagmus and that being induced by ice water test were summarized and analyzed 72h after model establishment in rats with different degrees of hemorrhage. The pressure of the cisternal magna and spinal subarachnoid space along with their difference were also monitored after the model establishment. It was explored the feasibility of the ENG being applied for monitoring the changing conditions of patients and for anticipating the formation of brain herniation after the cerebellar hemorrhage occurred.
2 To observe the neurotransmitter receptors such as GABA-ARα1 and NMDAR1 in brainstem nerve nucleus related eye movements of our rat model, which including paramedian pontine reticular formation (PPRF)、vestibular nucleus (VN) and oculor motor nucleus (OMN). To observe the neurochemistry mechanism of the changes of the spontaneous nystagmus and the abnormal nystagmus induced by ice water test through the neurotransmitters receptors of nucleus about eye movements and histological changes being measured in brainstem.
3 To explore the pathophysiological mechanisms of the spontaneous nystagmus and the abnormal nystagmus induced by ice water test after cerebellar hemorrhage through oberserving the changes of GABA-ARα1 and NMDAR1 in vestibular nucleus and recording the ENG of the fastigial nucleus (FN) and the flocculonodular lobe (FL) after electrical stimulation and being damaged by electrical coagulation.
Methods
Part I: Establishment of the cerebellar hemorrhage model and analysis of ENG
1TypeⅦcollagenase was injected into the dentate body of cerebellum in rats under stereotaxis according the method reported by Rosenberg. The rats were randomly divided into five groups:sham group, 0.2U injection group, 0.4U injection group, 0.6U injection group, 0.8U injection group, eight rats in each group.
2 The spontaneous nystagmus and nystagmus induced by ice water test were recorded through RM6240C multiple channel electrophysiolograph 72h after the model being established.
3 The pressure of the cisternal magna and spinal subarachnoid space were monitored 72h after the model being established. The pressure difference (dp) between them was also calculated.
4 The brain was fixed through 4℃paraformaldehyde perfused into the rats 72h after cerebellar hemorrhage model being established. Cerebellum and brainstem were removed. The coronal section of cerebellum were done by microtome behind and front along the puncture plane. The brainstem coronal sections were made the same as that. The HE staining was performed in the sections for observing pathological change.The hematoma area was calculated through formula.
5 Rats were killed 72h after cerebellar hemorrhage model established. The skull was removed and the cerebellum and brainstem were abstracted. Brain water content was measured through WBC way.
Part II: The neurochemistrical mechanisms of the spontaneous nystagmus and nystagmus induced by ice water test after cerebellar hemorrhage
1 The expressions of NMDAR1 and GABA-ARα1 were observed through immunohistochemistry in PPRF, VN, OMN in brainstem at 72h after cerebellar hemorrhage model being erected.
2 The histological and pathological changes of brainstems and cerebellums were observed through HE stainning at 72h after cerebellar hemorrhage model being erected.
Part III: spontaneous nystagmus and nystagmus induced by ice water test after the fastigial nucleus and the flocculonodular lobe being electric stimulated and electric coagulated damaged in rats
The ENG of the spontaneous nystagmus and nystagmus induced by ice water test were recored through RM6240C multiple channel electrophysiolograph of the fastigial nucleus and the flocculonodular lobe after the electrical stimulation and being damaged by electrical coagulation in rats. The expressions of NMDAR1 and GABA-ARα1 were observed through immunohistochemistry in VN.
Results
Part I
1 Animal survival rate: 8 rats died among the 40 rats including one for overdose of anesthesia, the others for brain herniation. Animal survival rate was 87.5%.
2 The pressure of the cisternal magna and spinal subarachnoid space: The pressure of the cisternal magna and spinal subarachnoid space were different among the 0.2U collagenase group, 0.4U collagenase group, 0.6U collagenase group and 0.8U collagenase group compared with the sham group (P<0.05). The higher doses of collagenase injected, the higher the pressure were, the greater dp between the pressure of cisternal magna and the pressure of spinal subarachnoid space (P<0.05).
3 Spontaneous nystagmus 72h after cerebellar hemorrhage in rats: spontaneous nystagmus was not observed in sham group. ENG recorded a smooth sine curve for the eye movements, no sawtooth nystagmus-like. All cerebellar hemorrhage model rats showed spontaneous nystagmus. Rotatory nystagmus were observed in horizontal direction of ENG for the fast phase to the left, slow phase to the right, the vertical upward direction for the fast phase and slow phase-down nystagmus in 0.2U group. 0.4U group also showed rotatory nystagmus, the direction being opposite to that of the 0.2U group. 0.6U group appeared spontaneous nystagmus which the fast phase to left and slow phase to the right, accompanied vertical nystagmus attacking intermittently which the fast phase and slow phase were down or up. The eyes fixed in 0.8U group rats and spontaneous nystagmus were not recorded which ENG showed a straight line.
4 Nystagmus induced by ice water 72h after cerebellar hemorrhage in rats: The horizontal nystagmus was induced by one lateral ice water injected to the ear which the fast phase directed to the contralateral to the lateral of ice water being injected and the slow phase directed to the the lateral of ice water being injected in sham group rats. The horizontal nystagmus was induced by ice water injected to the right ear which the fast phase directed to the left and the slow phase directed to the right in 0.2U group. The latency (Lat) was same (P>0.05), the frenquency(F)(P<0.05), the amplitude (Amp), the slow phase velocity (SPV) and the circadian variation index (CVI) were higher compared with sham group (P<0.01). The horizontal nystagmus was induced by ice water injected to the left ear which the fast phase directed to the right and the slow phase directed to the left in 0.2U group. The Lat was longer (P<0.01), F, Amp, SPV were lower (P<0.05), the CVI were higher compared with sham group (P<0.01). The horizontal nystagmus was induced by ice water injected to the right ear which the direction was same to 0.2U group which the Lat was longer (P<0.01), Amp (P<0.05), F, SPV were lower (P<0.01), the CVI were higher compared with sham group (P<0.01) in 0.4U group. While ice water being injected to the left ear, the nystagmus being induced which Lat was same (P>0.05), F, Amp, SPV and the CVI were higher compared with sham group (P<0.01). The horizontal nystagmus was induced by ice water injected to the right ear which the fast phase directed to the left and the slow phase directed to the right which Lat was same (P>0.05), F, Amp (P<0.05), SPV and the CVI were higher compared with sham group (P<0.01) in 0.6U group. The nystagmus was not induced by left ice water test in 0.6U group. Bilateral ice water test were failure in 0.8U group.
5 HE staining of the cerebellum in general : The side of the cerebellar hemisphere injected with the collagenase was engorage and full, in which part of them showed downward displacement and the midline shift to the opposite side. Brainstems of part of the rats were distorted. The injection needle track was seen without hematoma and edema in sham group rats. The hematoma was seen in the coronal section of cerebellum of each model rat. The center of hematoma showed madder red and the distinction between the grey and white matter was obscure. The bleeding part was close to each other in the model groups. The greater area of the hematoma was associated with increasing dosage of the collagenase injected (P<0.05).
6 Brain water content: The BWC was greater in each model group than the sham group (P<0.05). The correlation between the BWC and the dose of collagenase injection was positive (P<0.05). The injected dosage of collagenase was related to the BWC and cerebral edema.
PartⅡ
1 Expressions of neurotransmitters in the nucleus about eye movements: The positive cells which membrane was brownish through DAB stained distributed cluster-like in the brainstem. The distribution of inhibitory neurotransmitter ratio (GABA-ARα1/GABA-ARα1+NMDAR1) and excitatory neurotransmitter ratio (NMDAR1/GABA-ARα1+NMDAR1) within PPRF, VN, and OMN of both sides were no difference in the sham group (P>0.05). Excitatory neurotransmitter expressed higher on the right PPRF than the left PPRF in 0.2U collagenase group (P<0.05), which were higher in the left OMN and VN than the right OMN and VN (P<0.05). Excitatory neurotransmitter expressed higher on the left PPRF than the right PPRF in 0.4U collagenase group (P<0.05), which were higher in the right OMN and VN than the left OMN and VN (P<0.05). Excitatory neurotransmitters expressed higher on the right PPRF than the left PPRF in 0.6U collagenase group (P<0.05), excitatory neurotransmitter which were higher in the left OMN and VN than the right OMN and VN (P<0.05). The expressions of the excitory and inhibitory neurotransmitters in the nucleus all decreased in 0.8U group compared with sham and the other model groups. Excitatory neurotransmitters was higher in the right PPRF than in the left (P<0.05), which were higher in the left OMN and VN of than the right (P<0.05).
2 The pathological changes of cerebellum and brainstem in rats: The central of the hematoma was seen that the great deal of red cells and inflammatory cells were aggregaed. The neurons were swell which kytoplasm were rarefacted and the structure of the neuro fibries were disorder. The pathological phenomenons were obviously along the more collagenase injected. The HE stainning showed the histology of brainstem were normal in the rats of 0.2U and 0.4U group while were abnormal in the rats which died in 0.6U group and the rats of 0.8U group. The abnomal stainning showed the structure of neuro fibries were discontinued and disordered and the cellular nucleus of neurons were disappeared. The pathological changes showed seriously near the middle line of the brainstem.
PartⅢ
1 Spontaneous nystagmus and nystagmus induced by ice water after the flocculonodular lobe after electrical stimulation in rats
All rats showed spontaneous nystagmus. Rotational nystagmus were observed in horizontal direction of ENG for the fast phase to the left, slow phase to the right, the vertical upward direction for the fast phase and slow phase-down nystagmus. The horizontal nystagmus was induced by ice water injection to the right ear, which the direction and the Lat was no significant difference compared with the control group (P>0.05), whereas the F, Amp, SPV and the CVI were higher compared with the control group (P<0.01). The direction of the nystagmus was opposite to that of the right lateral ice water test by left lateral ice water test, which the Lat was longer (P<0.01), the F, Amp, SPV were lower (P<0.01) and CVI was higher compared with control group (P<0.01).
2 Spontaneous nystagmus and nystagmus induced by ice water after the flocculonodular lobe being damaged by electrical coagulation in rats
All rats showed spontaneous nystagmus. Rotatory nystagmus were observed in horizontal direction of ENG for the fast phase to the right, slow phase to the left, the vertical upward direction for the fast phase and slow phase-down nystagmus. The horizontal nystagmus was induced by ice water injection to the right ear which the direction was same to the control group while the Lat was longer, The F, Amp, SPV were lower compared with control group (P<0.01) and the CVI was higher (P<0.01). The horizontal nystagmus was induced by ice water injected to the left ear which the fast phase directed to the right and the slow phase directed to the left which Lat was same (P>0.05). F, Amp, SPV (P<0.01) and the CVI were higher compared with control group (P<0.01).
3 Spontaneous nystagmus and nystagmus induced by ice water after the fastigial nucleus being electric stimulated in rats
All rats showed spontaneous nystagmus. Rotatory nystagmus were observed in horizontal direction of ENG for the fast phase to the right, slow phase to the left, the vertical upward direction for the fast phase and slow phase-down nystagmus. The horizontal nystagmus was induced by ice water injected to the right ear which the direction was same to the control group which the Lat was longer, the F, Amp, SPV were lower compared with control group (P<0.01) and the CVI was higher (P<0.01). The horizontal nystagmus was induced by ice water injected to the left ear which the fast phase directed to the right and the slow phase directed to the left which Lat was same (P>0.05). The F, Amp, SPV and the CVI were higher compared with control group (P<0.01).
4 Spontaneous nystagmus and nystagmus induced by ice water after the fastigial nucleus being damaged by electrical coagulation in rats
All rats showed spontaneous nystagmus. Rotatory nystagmus were observed in horizontal direction of ENG for the fast phase to the left, slow phase to the right, the vertical upward direction for the fast phase and slow phase-down nystagmus. The horizontal nystagmus was induced by ice water injected to the right ear which the direction and the Lat were no significant difference compared with the control group (P>0.05). The F, Amp, SPV and the CVI were higher compared with the control group (P<0.01). The direction of the nystagmus was opposite to that of the right lateral ice water test by left lateral ice water test, which the Lat was longer, the F, Amp, SPV were lower (P<0.01) and CVI was higher compared with control group (P<0.01).
5 After the right flocculonodular lobe being stimulated, excitatory neurotransmitter ratio was lower in the right VN than the left VN (P<0.05). After the destruction of the right flocculonodular lobe, excitatory neurotransmitter ratio was higher in the right VN than the left (P<0.05).
6 After the right fastigial nucleus being stimulated, excitatory neurotransmitter ratio was higher in the right VN than the left VN (P <0.05). After the destruction of the right fastigial nucleus, excitatory neurotransmitter ratio was higher in the left VN than the right (P<0.05).
Conclusions
1 Cerebellar hemorrhage model can be established successfully through the injection of collagenase into cerebellar dentate nuclei of rat under stereotaxis. The hematoma area was increased along the increasing injection dose of collagenase.
2 Different forms of spontaneous nystagmus and nystagmus induced by ice water could be showed in the cerebellar hemorrhage model with different amount of bleeding.
3 Different amount of bleeding in the cerebellum could affected the brainstem in different extent. Brainstem function could be determined according the different variations of nystagmus after cerebellar hemorrhage.
4 PCM, PSSS increased and the pressure difference between them may be the possible causes of changes in nystagmus after cerebellar hemorrhage.
在我国的城镇居民中,脑血管疾病已成为患者死亡的首要原因,其中颅内出血(intracerebral homorrhage,ICH)约占脑卒中患者的15%,发病一个月内死亡率约为50%,而且发病年龄越来越年轻化。在ICH患者中,有5-10%的患者出血部位在小脑,最终致死率高达20-30%。通过尸检发现,小脑出血患者的死亡主要是出血和水肿形成脑疝,造成对脑干的压迫和破坏所引起的。所以及早判定患者病情变化和及时采取临床干预措施是治疗疾病、挽救生命的关键。
目前,脑CT是诊断小脑出血最可靠的检查方法,但它较少用于连续动态检查,如果反复检查,费用较高,且需要运送患者,在不方便的同时也可能引起患者病情的恶化。现在,在临床上缺乏对小脑出血患者的病情发展进行床旁动态监测及对病情是否波及脑干进行预判的方法和手段。本实验研究一种临床监测手段,它具有床旁、动态、无创、简单、客观、准确的优点。最重要的是,它既能够在小脑出血和水肿侵犯脑干时进行判断,又能够监测小脑出血和水肿对脑干由刺激到破坏的动态过程,为临床医生及时判断患者病情变化和及早进行临床干预提供了可能。
目的
1建立稳定的小脑半球出血大鼠模型,观察和总结不同程度出血大鼠在术后72h的自发眼震和冰水诱发眼震电图( ENG ,electronystagmogram)的变化特点和规律,观察模型大鼠枕大池压力(pressure of cisterna magna,PCM)和脊髓蛛网膜下腔压力(pressure of spinal subarachnoid space,PSSS)及压力差,探讨利用ENG监测小脑出血病情变化和预先判断小脑脑疝发生的可行性。
2观察小脑半球出血模型大鼠脑干眼动相关神经核团(脑桥旁正中网状结构(paramedian pontine reticular formation,PPRF)、前庭神经核(vestibular nucleus,VN)和动眼神经核(oculor motor nucleus,OMN))的神经递质受体GABA-ARα1和NMDAR1变化及相关神经核团的HE染色变化,探讨小脑半球出血继发脑干病变引起自发眼震和冰水诱发眼震异常的神经化学机制。
3观察电刺激及电凝损毁大鼠小脑绒球小结叶(flocculonodular lobe,FL)和顶核(fastigial nucleus,FN)后自发和冰水诱发ENG变化及VN神经递质受体GABA-ARα1和NMDAR1变化,通过与小脑出血引起眼震异常的比较及对VN神经递质受体变化的分析,探讨小脑半球出血引起自发眼震和冰水诱发眼震异常的病理生理基础。
方法
第一部分:小脑半球出血大鼠模型的建立及对眼球震颤的分析
1根据Rosenberg报道的方法,立体定位小脑齿状核,注射Ⅶ型胶原酶建立小脑半球出血大鼠模型。动物随机分为5组:假手术组、0.2UⅦ型胶原酶组、0.4UⅦ型胶原酶组、0.6UⅦ型胶原酶组、0.8UⅦ型胶原酶组,每组8只。在小脑半球出血大鼠模型建立72h时,采集以下指标
2使用RM6240C多道生理记录仪记录其自发和冰水诱发ENG。
3分别测量其枕大池和脊髓蛛网膜下腔压力,并计算二者间的压力差。
4使用4℃多聚甲醛灌注固定大鼠,取出脑组织,以针道所在中心,穿刺平面前后,切片机作冠状切片,常规HE染色,根据公式计算血肿面积。
5处死大鼠,剥离颅骨取出脑组织,分离脑干和小脑,使用干湿重法测定小脑半球出血后脑组织含水量。
第二部分:小脑半球出血模型大鼠自发和冰水诱发眼震的神经化学机制研究
1通过免疫组化法观察模型大鼠PPRF、VN和OMN抑制性神经递质受体GABA-ARα1和兴奋性神经递质受体NMDAR1变化情况。
2通过HE染色镜下观察模型大鼠小脑及脑干组织病理学改变。第三部分:大鼠一侧小脑绒球小结叶和顶核电刺激及电凝损毁后眼震电图变化
电刺激及电凝损毁大鼠一侧小脑绒球小结叶和顶核,观察其自发眼震和冰水诱发ENG改变及脑干VN神经递质变化。
结果
第一部分:1动物存活率:40只实验大鼠共死亡8只,其中1只因麻醉过量死亡,另外7只死于脑疝,动物存活率为87.5%。
2 PCM、PSSS和两者间的压力差:在术后72h时,0.2U组、0.4U组、0.6U组和0.8U组大鼠PCM、PSSS与假手术组大鼠相比有明显差异(P<0.05),胶原酶注入剂量越大,大鼠PCM、PSSS越高,二者间压力差越大(P<0.05)。
3大鼠模型建立72h自发眼震:在假手术组大鼠未观察到自发震颤,ENG记录可见正弦平滑曲线为扫视眼球运动,未见眼震样锯齿波。所有胶原酶诱导小脑出血模型组大鼠72h均出现自发性眼震。0.2U组大鼠可观察到旋转性眼震,在ENG上为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震;0.4U组大鼠也表现为旋转性眼震,其方向与0.2U组大鼠相反;0.6U组大鼠出现了快相向左,慢相向右的水平性自发性眼震,伴有间断性发作的快相向上、慢相向下或者快相向下、慢相向上的垂直性眼震;0.8U组大鼠死亡前眼球固定,未记录到自发眼震,ENG呈一条直线。
4大鼠模型建立72h冰水诱发眼震:假手术组大鼠一侧冰水诱发后可见快相向冰水对侧,慢相向冰水侧的水平跳动性眼震。0.2U组大鼠右侧冰水诱发为快相向左、慢相向右的水平为主伴有垂直方向的眼震,其潜伏期(Lat,latency)与假手术组比较无差异(P>0.05),频率(F,Frequency)(P<0.05)、波幅(Amp,amplitude)、慢相角速度(SPV,slow-phase velocity)及变异系数(CVI,circadian variation index)均高于假手术组(P<0.01)。左侧冰水诱发眼震在水平方向上与右侧冰水诱发方向相反,Lat较假手术组延长(P<0.01),F、Amp、SPV均低于假手术组(P<0.05),CVI增大(P<0.01)。0.4U组大鼠右侧冰水诱发眼震在水平方向上与0.2U组相同,Lat较假手术组延长(P<0.01),Amp(P<0.05)、F、SPV均低于假手术组(P<0.01),CVI增大(P<0.01);左侧冰水诱发眼震在水平方向上与0.2U组相同,Lat与假手术组比较无差异(P>0.05),F、Amp、SPV及CVI均高于假手术组(P<0.01)。0.6U组大鼠右侧冰水诱发眼震在水平方向上为快相向左,慢相向右的眼震,Lat与假手术组比较无差异(P>0.05),F、Amp(P<0.05)、SPV及CVI均高于假手术组(P<0.01);左侧冰水刺激未诱发出眼震。0.8U组大鼠双侧冰水刺激均未诱发眼震。
5大鼠小脑血肿面积:各造模组大鼠在72h可见注入胶原酶一侧小脑半球肿胀、饱满;部分大鼠脑组织出现移位,中线向对侧偏移,脑干受压扭曲变形。假手术组大鼠注射侧脑组织仅见注射针道,未见血肿及水肿。各造模组可见小脑半球出血,出血中心呈暗红色,出血部位相近,分布均一,周围灰白质分界模糊。不同剂量胶原酶组形成的血肿面积大小不同,其组间对比有统计学差异(P<0.05),注入胶原酶剂量越多,血肿面积越大。
6脑组织含水量:胶原酶注射各组大鼠脑组织含水量测定明显高于假手术组(P<0.05)。胶原酶注射各组大鼠脑组织含水量与胶原酶剂量呈正相关(P<0.05),即胶原酶注入剂量越大,脑组织含水量越多,脑水肿越明显。
第二部分:1脑干眼动相关神经核团递质变化:细胞膜被DAB染成棕黄的阳性细胞在脑干内呈群集样分布,抑制神经递质比( GABA-ARα1/GABA-ARα1+ NMDAR1 )和兴奋神经递质比(NMDAR1/ GABA-ARα1+ NMDAR1)在假手术组脑干两侧PPRF、VN和OMN内无差别(P>0.05);0.2U组大鼠脑干右侧PPRF兴奋神经递质比高于左侧(P<0.05),左侧OMN和VN兴奋神经递质高于右侧(P<0.05);0.4U组大鼠脑干左侧PPRF兴奋神经递质比高于右侧(P<0.05),右侧OMN和VN兴奋神经递质高于左侧(P<0.05);0.6U组大鼠脑干右侧PPRF兴奋神经递质比高于左侧(P<0.05),左侧OMN和VN兴奋神经递质高于右侧(P<0.05);0.8U组大鼠脑干PPRF、VN和OMN神经递质较假手术组及其他造模组表达下降,但右侧PPRF和兴奋神经递质比相对高于左侧(P<0.05),左侧OMN和VN兴奋神经递质相对高于右侧(P<0.05)。
2模型大鼠小脑及脑干组织病理学:光镜下观察HE染色可见造模侧血肿区域内大量红细胞及炎性细胞聚集,血肿中心及周围神经细胞肿胀,体积增大,周围出现空隙;神经纤维排列紊乱、中断、疏松;部分小血管闭塞。胶原酶注入剂量越大,红细胞及炎性细胞聚集越明显,组织疏松水肿范围越大。0.2U及0.4U组大鼠脑干HE染色与假手术组对照无异常,在0.6U组因脑疝死亡的大鼠及0.8U组大鼠的脑干中,可见脑干中纵行和横行的神经纤维组织紊乱、中断及疏松,以脑桥延髓阶段中线结构改变明显;炎性细胞聚集,胞核增大深染,嗜酸性增强,其间散在分布的神经细胞核群内部分细胞出现细胞肿胀,细胞核碎裂或脱失,此改变以脑桥及延髓阶段右侧明显。
第三部分:大鼠右侧绒球小结叶和顶核电刺激及电凝损毁后自发和冰水诱发眼震特点及ENG
1右侧小脑绒球小结叶电刺激后自发和冰水诱发眼震特点及ENG:为旋转性眼震,在ENG上为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震。右侧冰水诱发眼震在形式上表现为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震。ENG表现与正常对照组相比,Lat无差异(P>0.05),F加快、Amp增加,SPV增快和CVI增大(P<0.01);左侧冰水诱发眼震在形式上表现为水平方向上快相向右、慢相向左,垂直方向上为快相向上、慢相向下的眼震,ENG表现与正常对照组相比,Lat延长(P<0.01)、F减慢、Amp和SPV减小(P<0.01),CVI增大(P<0.01)。
2右侧绒球小结叶电凝损毁后自发和冰水诱发眼震特点及ENG:为旋转性眼震,在ENG上为水平方向上快相向右、慢相向左,垂直方向上为快相向上、慢相向下的眼震。右侧冰水诱发眼震在形式上表现为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震,ENG表现与正常对照组相比,Lat延长、F减慢、Amp和SPV减小(P<0.01),CVI增大(P<0.01);左侧冰水诱发眼震在形式上表现为水平方向上快相向右、慢相向左,垂直方向上为快相向上、慢相向下的眼震,ENG表现与正常对照组相比,Lat无差异(P>0.05),F增加、Amp、SPV增大(P<0.01)和CVI增大(P<0.01)。
3右侧顶核电刺激后自发和冰水诱发眼震特点及ENG:大鼠右侧顶核电刺激后出现了快相向右,慢相向左的水平性自发性眼震,伴有间断性发作的快相向上、慢相向下或者快相向下、慢相向上的垂直性眼震。右侧冰水诱发眼震在水平方向上与正常对照组比较无差异,Lat延长,F、Amp、SPV均低于对照组(P<0.01),CVI高于对照组(P<0.01)。左侧冰水诱发表现为快相向右,慢相向左的水平眼震,Lat与正常对照组比较无统计学差异(P>0.05),F、Amp、SPV及CVI均高于正常对照组(P<0.01)。
4右侧顶核电凝损毁后可观察到旋转性眼震,在ENG上为水平方向上快相向左、慢相向右,垂直方向上为快相向上、慢相向下的眼震。右侧冰水诱发眼震在水平方向上表现为快相向左、慢相向右的眼震,Lat与正常对照组比较无统计学差异(P>0.05),F、Amp、SPV及CVI均高于正常对照组(P<0.01)。左侧冰水刺激诱发眼震在形式上方向与右侧冰水相反,但Lat延长,F、Amp、SPV均低于对照组(P<0.01),CVI增大(P<0.01)。
5右侧绒球小节叶电剌激,脑干右侧VN兴奋神经递质比低于左侧(P<0.05),右侧绒球小节叶电凝损毁后,脑干右侧VN兴奋神经递质比高于左侧(P<0.05)。
6右侧顶核电剌激,脑干右侧VN兴奋神经递质比高于左侧(P<0.05),右侧顶核电凝损毁后,脑干右侧VN兴奋神经递质比低于左侧(P<0.05)。
结论
1应用不同剂量胶原酶立体定向注入大鼠小脑齿状核可以成功构建不同出血量的小脑出血动物模型。
2大鼠小脑的出血量不同,自发眼震和冰水诱发眼震的表现形式也不同。
3大鼠小脑不同的出血量对脑干形成不同的影响,而根据眼震尤其是冰水诱发眼震的不同变化形式可以判定小脑出血后脑干的功能状态。
4 PCM、PSSS升高及两者压力差的存在可能是小脑出血后眼震发生变化的原因。
Background
Cerebrovascular disease is the leading death cause of urban residents in China. Intracranial hemorrhage (intracerebral hemorrhage, ICH) accounts for about 15% of stroke patients, with the mortality about 50% within the first month after attack. The incidence age has become much younger in recent years. The ICH bleeding location of 5-10% of patients is in the cerebellum with the final mortality rate as high as 20-30%. Autopsy studies showed that death of cerebellar hemorrhage was mainly caused by herniation by which the brainstem was oppressed and destructed under the circumstance of the hemorrhage and edema. Therefore, it was critical to monitor the changes of patients’condition and apply early interventional strategy to treated the disease and save lives. At present, CT is the most reliable detecting method for the diagnosis of the cerebellar hemorrhage. However, CT is not a dynamic diagnostic method, whereas the repeated exam to observe the changing condition of the patients increase the the costs. Another disadvantage is the movement of the patients may worse the condition of the patients. A method which can be operated bedside in time is largely needed to monitor the progression of the patients’condition which to discriminate whether the brainstem was intact. The study was to find a clinical useful monitoring method which has the characteristics including bedside, dynamic, non-invasive, simple, objective, accurate. Importantly, it is that it can be applied to anticipate the occurrence of brainstem intact after cerebellar hemorrhage and monitor the dynamic process of the brainstem intact which changed from being stimulated to being damaged.
Purposes
1 The stable cerebellar hemorrhage model in rats was established. The characteristics and changing pattern of electronystagmogram spontaneous nystagmus and that being induced by ice water test were summarized and analyzed 72h after model establishment in rats with different degrees of hemorrhage. The pressure of the cisternal magna and spinal subarachnoid space along with their difference were also monitored after the model establishment. It was explored the feasibility of the ENG being applied for monitoring the changing conditions of patients and for anticipating the formation of brain herniation after the cerebellar hemorrhage occurred.
2 To observe the neurotransmitter receptors such as GABA-ARα1 and NMDAR1 in brainstem nerve nucleus related eye movements of our rat model, which including paramedian pontine reticular formation (PPRF)、vestibular nucleus (VN) and oculor motor nucleus (OMN). To observe the neurochemistry mechanism of the changes of the spontaneous nystagmus and the abnormal nystagmus induced by ice water test through the neurotransmitters receptors of nucleus about eye movements and histological changes being measured in brainstem.
3 To explore the pathophysiological mechanisms of the spontaneous nystagmus and the abnormal nystagmus induced by ice water test after cerebellar hemorrhage through oberserving the changes of GABA-ARα1 and NMDAR1 in vestibular nucleus and recording the ENG of the fastigial nucleus (FN) and the flocculonodular lobe (FL) after electrical stimulation and being damaged by electrical coagulation.
Methods
Part I: Establishment of the cerebellar hemorrhage model and analysis of ENG
1TypeⅦcollagenase was injected into the dentate body of cerebellum in rats under stereotaxis according the method reported by Rosenberg. The rats were randomly divided into five groups:sham group, 0.2U injection group, 0.4U injection group, 0.6U injection group, 0.8U injection group, eight rats in each group.
2 The spontaneous nystagmus and nystagmus induced by ice water test were recorded through RM6240C multiple channel electrophysiolograph 72h after the model being established.
3 The pressure of the cisternal magna and spinal subarachnoid space were monitored 72h after the model being established. The pressure difference (dp) between them was also calculated.
4 The brain was fixed through 4℃paraformaldehyde perfused into the rats 72h after cerebellar hemorrhage model being established. Cerebellum and brainstem were removed. The coronal section of cerebellum were done by microtome behind and front along the puncture plane. The brainstem coronal sections were made the same as that. The HE staining was performed in the sections for observing pathological change.The hematoma area was calculated through formula.
5 Rats were killed 72h after cerebellar hemorrhage model established. The skull was removed and the cerebellum and brainstem were abstracted. Brain water content was measured through WBC way.
Part II: The neurochemistrical mechanisms of the spontaneous nystagmus and nystagmus induced by ice water test after cerebellar hemorrhage
1 The expressions of NMDAR1 and GABA-ARα1 were observed through immunohistochemistry in PPRF, VN, OMN in brainstem at 72h after cerebellar hemorrhage model being erected.
2 The histological and pathological changes of brainstems and cerebellums were observed through HE stainning at 72h after cerebellar hemorrhage model being erected.
Part III: spontaneous nystagmus and nystagmus induced by ice water test after the fastigial nucleus and the flocculonodular lobe being electric stimulated and electric coagulated damaged in rats
The ENG of the spontaneous nystagmus and nystagmus induced by ice water test were recored through RM6240C multiple channel electrophysiolograph of the fastigial nucleus and the flocculonodular lobe after the electrical stimulation and being damaged by electrical coagulation in rats. The expressions of NMDAR1 and GABA-ARα1 were observed through immunohistochemistry in VN.
Results
Part I
1 Animal survival rate: 8 rats died among the 40 rats including one for overdose of anesthesia, the others for brain herniation. Animal survival rate was 87.5%.
2 The pressure of the cisternal magna and spinal subarachnoid space: The pressure of the cisternal magna and spinal subarachnoid space were different among the 0.2U collagenase group, 0.4U collagenase group, 0.6U collagenase group and 0.8U collagenase group compared with the sham group (P<0.05). The higher doses of collagenase injected, the higher the pressure were, the greater dp between the pressure of cisternal magna and the pressure of spinal subarachnoid space (P<0.05).
3 Spontaneous nystagmus 72h after cerebellar hemorrhage in rats: spontaneous nystagmus was not observed in sham group. ENG recorded a smooth sine curve for the eye movements, no sawtooth nystagmus-like. All cerebellar hemorrhage model rats showed spontaneous nystagmus. Rotatory nystagmus were observed in horizontal direction of ENG for the fast phase to the left, slow phase to the right, the vertical upward direction for the fast phase and slow phase-down nystagmus in 0.2U group. 0.4U group also showed rotatory nystagmus, the direction being opposite to that of the 0.2U group. 0.6U group appeared spontaneous nystagmus which the fast phase to left and slow phase to the right, accompanied vertical nystagmus attacking intermittently which the fast phase and slow phase were down or up. The eyes fixed in 0.8U group rats and spontaneous nystagmus were not recorded which ENG showed a straight line.
4 Nystagmus induced by ice water 72h after cerebellar hemorrhage in rats: The horizontal nystagmus was induced by one lateral ice water injected to the ear which the fast phase directed to the contralateral to the lateral of ice water being injected and the slow phase directed to the the lateral of ice water being injected in sham group rats. The horizontal nystagmus was induced by ice water injected to the right ear which the fast phase directed to the left and the slow phase directed to the right in 0.2U group. The latency (Lat) was same (P>0.05), the frenquency(F)(P<0.05), the amplitude (Amp), the slow phase velocity (SPV) and the circadian variation index (CVI) were higher compared with sham group (P<0.01). The horizontal nystagmus was induced by ice water injected to the left ear which the fast phase directed to the right and the slow phase directed to the left in 0.2U group. The Lat was longer (P<0.01), F, Amp, SPV were lower (P<0.05), the CVI were higher compared with sham group (P<0.01). The horizontal nystagmus was induced by ice water injected to the right ear which the direction was same to 0.2U group which the Lat was longer (P<0.01), Amp (P<0.05), F, SPV were lower (P<0.01), the CVI were higher compared with sham group (P<0.01) in 0.4U group. While ice water being injected to the left ear, the nystagmus being induced which Lat was same (P>0.05), F, Amp, SPV and the CVI were higher compared with sham group (P<0.01). The horizontal nystagmus was induced by ice water injected to the right ear which the fast phase directed to the left and the slow phase directed to the right which Lat was same (P>0.05), F, Amp (P<0.05), SPV and the CVI were higher compared with sham group (P<0.01) in 0.6U group. The nystagmus was not induced by left ice water test in 0.6U group. Bilateral ice water test were failure in 0.8U group.
5 HE staining of the cerebellum in general : The side of the cerebellar hemisphere injected with the collagenase was engorage and full, in which part of them showed downward displacement and the midline shift to the opposite side. Brainstems of part of the rats were distorted. The injection needle track was seen without hematoma and edema in sham group rats. The hematoma was seen in the coronal section of cerebellum of each model rat. The center of hematoma showed madder red and the distinction between the grey and white matter was obscure. The bleeding part was close to each other in the model groups. The greater area of the hematoma was associated with increasing dosage of the collagenase injected (P<0.05).
6 Brain water content: The BWC was greater in each model group than the sham group (P<0.05). The correlation between the BWC and the dose of collagenase injection was positive (P<0.05). The injected dosage of collagenase was related to the BWC and cerebral edema.
PartⅡ
1 Expressions of neurotransmitters in the nucleus about eye movements: The positive cells which membrane was brownish through DAB stained distributed cluster-like in the brainstem. The distribution of inhibitory neurotransmitter ratio (GABA-ARα1/GABA-ARα1+NMDAR1) and excitatory neurotransmitter ratio (NMDAR1/GABA-ARα1+NMDAR1) within PPRF, VN, and OMN of both sides were no difference in the sham group (P>0.05). Excitatory neurotransmitter expressed higher on the right PPRF than the left PPRF in 0.2U collagenase group (P<0.05), which were higher in the left OMN and VN than the right OMN and VN (P<0.05). Excitatory neurotransmitter expressed higher on the left PPRF than the right PPRF in 0.4U collagenase group (P<0.05), which were higher in the right OMN and VN than the left OMN and VN (P<0.05). Excitatory neurotransmitters expressed higher on the right PPRF than the left PPRF in 0.6U collagenase group (P<0.05), excitatory neurotransmitter which were higher in the left OMN and VN than the right OMN and VN (P<0.05). The expressions of the excitory and inhibitory neurotransmitters in the nucleus all decreased in 0.8U group compared with sham and the other model groups. Excitatory neurotransmitters was higher in the right PPRF than in the left (P<0.05), which were higher in the left OMN and VN of than the right (P<0.05).
2 The pathological changes of cerebellum and brainstem in rats: The central of the hematoma was seen that the great deal of red cells and inflammatory cells were aggregaed. The neurons were swell which kytoplasm were rarefacted and the structure of the neuro fibries were disorder. The pathological phenomenons were obviously along the more collagenase injected. The HE stainning showed the histology of brainstem were normal in the rats of 0.2U and 0.4U group while were abnormal in the rats which died in 0.6U group and the rats of 0.8U group. The abnomal stainning showed the structure of neuro fibries were discontinued and disordered and the cellular nucleus of neurons were disappeared. The pathological changes showed seriously near the middle line of the brainstem.
PartⅢ
1 Spontaneous nystagmus and nystagmus induced by ice water after the flocculonodular lobe after electrical stimulation in rats
All rats showed spontaneous nystagmus. Rotational nystagmus were observed in horizontal direction of ENG for the fast phase to the left, slow phase to the right, the vertical upward direction for the fast phase and slow phase-down nystagmus. The horizontal nystagmus was induced by ice water injection to the right ear, which the direction and the Lat was no significant difference compared with the control group (P>0.05), whereas the F, Amp, SPV and the CVI were higher compared with the control group (P<0.01). The direction of the nystagmus was opposite to that of the right lateral ice water test by left lateral ice water test, which the Lat was longer (P<0.01), the F, Amp, SPV were lower (P<0.01) and CVI was higher compared with control group (P<0.01).
2 Spontaneous nystagmus and nystagmus induced by ice water after the flocculonodular lobe being damaged by electrical coagulation in rats
All rats showed spontaneous nystagmus. Rotatory nystagmus were observed in horizontal direction of ENG for the fast phase to the right, slow phase to the left, the vertical upward direction for the fast phase and slow phase-down nystagmus. The horizontal nystagmus was induced by ice water injection to the right ear which the direction was same to the control group while the Lat was longer, The F, Amp, SPV were lower compared with control group (P<0.01) and the CVI was higher (P<0.01). The horizontal nystagmus was induced by ice water injected to the left ear which the fast phase directed to the right and the slow phase directed to the left which Lat was same (P>0.05). F, Amp, SPV (P<0.01) and the CVI were higher compared with control group (P<0.01).
3 Spontaneous nystagmus and nystagmus induced by ice water after the fastigial nucleus being electric stimulated in rats
All rats showed spontaneous nystagmus. Rotatory nystagmus were observed in horizontal direction of ENG for the fast phase to the right, slow phase to the left, the vertical upward direction for the fast phase and slow phase-down nystagmus. The horizontal nystagmus was induced by ice water injected to the right ear which the direction was same to the control group which the Lat was longer, the F, Amp, SPV were lower compared with control group (P<0.01) and the CVI was higher (P<0.01). The horizontal nystagmus was induced by ice water injected to the left ear which the fast phase directed to the right and the slow phase directed to the left which Lat was same (P>0.05). The F, Amp, SPV and the CVI were higher compared with control group (P<0.01).
4 Spontaneous nystagmus and nystagmus induced by ice water after the fastigial nucleus being damaged by electrical coagulation in rats
All rats showed spontaneous nystagmus. Rotatory nystagmus were observed in horizontal direction of ENG for the fast phase to the left, slow phase to the right, the vertical upward direction for the fast phase and slow phase-down nystagmus. The horizontal nystagmus was induced by ice water injected to the right ear which the direction and the Lat were no significant difference compared with the control group (P>0.05). The F, Amp, SPV and the CVI were higher compared with the control group (P<0.01). The direction of the nystagmus was opposite to that of the right lateral ice water test by left lateral ice water test, which the Lat was longer, the F, Amp, SPV were lower (P<0.01) and CVI was higher compared with control group (P<0.01).
5 After the right flocculonodular lobe being stimulated, excitatory neurotransmitter ratio was lower in the right VN than the left VN (P<0.05). After the destruction of the right flocculonodular lobe, excitatory neurotransmitter ratio was higher in the right VN than the left (P<0.05).
6 After the right fastigial nucleus being stimulated, excitatory neurotransmitter ratio was higher in the right VN than the left VN (P <0.05). After the destruction of the right fastigial nucleus, excitatory neurotransmitter ratio was higher in the left VN than the right (P<0.05).
Conclusions
1 Cerebellar hemorrhage model can be established successfully through the injection of collagenase into cerebellar dentate nuclei of rat under stereotaxis. The hematoma area was increased along the increasing injection dose of collagenase.
2 Different forms of spontaneous nystagmus and nystagmus induced by ice water could be showed in the cerebellar hemorrhage model with different amount of bleeding.
3 Different amount of bleeding in the cerebellum could affected the brainstem in different extent. Brainstem function could be determined according the different variations of nystagmus after cerebellar hemorrhage.
4 PCM, PSSS increased and the pressure difference between them may be the possible causes of changes in nystagmus after cerebellar hemorrhage.
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